Is DEF6 p.Arg534His (c.1601G>A) pathogenic?

DEF6 p.Arg534His (c.1601G>A) is classified Uncertain significance in DEF6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-13). AlphaMissense: likely benign (0.0879); Very rare (popmax 0.00951%, nfe).

How common is DEF6 p.Arg534His (c.1601G>A) in the general population?

DEF6 p.Arg534His (c.1601G>A) is very rare (popmax 0.00951%, nfe) (gnomAD).

What do computational predictors say about DEF6 p.Arg534His (c.1601G>A)?

AlphaMissense predicts likely benign (score 0.0879) — an in-silico prediction, not a clinical call.

DEF6 p.Arg534His

c.1601G>A · rs747695494 · VCV1522981

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0879 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00951%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0879	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -6.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 24 kb · p 1.6e-17 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00951% European (non-Finnish) · 112/1,177,698 alleles

Filtering AF 0.00806% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00753%

Overall 0.00783% 126/1,609,722 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00951%	10,515
South Asian	0.00774%	12,912
Remaining individualsnot grpmax-eligible	0.00482%	20,768
African / African-American	0.00401%	24,924
Admixed American	0.00168%	59,618

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DEF6
Protein: p.Arg534His
Coding: c.1601G>A
MANE Select: NM_022047
dbSNP: rs747695494
Type: single nucleotide variant
Location: chr6:35320903 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91
Residue 534: a UniProt-annotated variant site (in imd87; protein not detected in homozygous patient t cells or when the mutant is expressed in a heterologous system); the 'disordered' region

Full DEF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEF6 p.Arg534Cys Uncertain significance ★ ⚠ same residue
DEF6 p.Arg534= Likely benign ★ same residue
DEF6 p.Ala395Glu Uncertain significance ★★ ⚠ same type
DEF6 p.Ala617Val Uncertain significance ★★ ⚠ same type
DEF6 p.Arg104Pro Uncertain significance ★★ ⚠ same type
DEF6 p.Arg104Trp Uncertain significance ★★ ⚠ same type
DEF6 p.Arg192Cys Uncertain significance ★★ ⚠ same type
DEF6 p.Arg195Gln Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/def6-p-arg534his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown